The present invention relates to an improved pharmaceutical composition comprising macromolecule pharmaceuticals in micellar form. The pharmaceutical compositions are particularly effective in buccal and pulmonary applications. The present invention further relates to methods for preparing and using these pharmaceutical compositions. Methods for enhancing the rate of absorption of a macromolecular pharmaceutical agent are also disclosed.
Relatively little progress has been made over the years in reaching the target of safe and effective oral formulations for macromolecules, including peptides and proteins. Barriers to developing oral formulations for proteins and peptides include poor intrinsic permeability, lumenal and cellular enzymatic degradation, rapid clearance, and chemical instability in the gastrointestinal (GI) tract. Pharmaceutical approaches to address these barriers that have been successful with traditional small, organic drug molecules have not readily translated into effective peptide and protein formulations.
Various routes of administration other than injection for proteins and peptides have been explored with little or no success. Oral and nasal cavities have been of particular interest. The ability of molecules to permeate the oral mucosae appears to be related to molecular size, lipid solubility and peptide protein ionization. Molecules less than 1000 daltons appear to cross oral mucosae rapidly. As molecular size increases, the permeability of the molecule decreases rapidly. Lipid soluble compounds are more permeable than non-lipid soluble molecules. Maximum absorption occurs when molecules are un-ionized or neutral in electrical charges. Charged molecules, therefore, present the biggest challenges to absorption through the oral mucosae.
Most proteinic drug molecules are extremely large molecules with molecular weights exceeding 6000 daltons. In addition to being large, these molecules typically have very poor lipid solubility, and are often practically impermeable. Substances that facilitate the absorption or transport of large molecules (i.e.,  greater than 1000 daltons) across biological membranes are referred to in the art as xe2x80x9cenhancersxe2x80x9d or xe2x80x9cabsorption aidsxe2x80x9d. These compounds generally include chelators, bile salts, fatty acids, synthetic hydrophilic and hydrophobic compounds, and biodegradable polymeric compounds. Many enhancers lack a satisfactory safety profile respecting irritation, lowering of the barrier function, and impairment of the mucocilliary clearance protective mechanism.
Some enhancers, especially those related to bile salts, and some protein solubilizing agents give an extremely bitter and unpleasant taste. This makes their use almost impossible for human consumption on a daily basis. Several approaches attempting to address the taste problem relating to the bile salt-based delivery systems include patches for buccal mucosa, bilayer tablets, controlled release tablets, use of protease inhibitors, and various polymer matrices. These technologies fail to deliver proteinic drugs in the required therapeutic concentrations, however. Further, the film patch devices result in severe tissue damage in the mouth. Other attempts to deliver large molecules via the oral, nasal, rectal, and vaginal routes using single bile acids or enhancing agents in combination with protease inhibitors and biodegradable polymeric materials similarly failed to achieve therapeutic levels of proteinic drugs in the patient. Single enhancing agents fail to loosen tight cellular junctions in the oral, nasal, rectal and vaginal cavities for the time needed to permit passage of large molecules through the mucosal membranes without further degradation. These problems make it impractical to use many systems. Accordingly, there remains a need for improved therapeutic formulations, particularly those comprising macromolecules and particularly those useful for buccal and pulmonary application. Methods for manufacture and use of such formulations are also needed.
The present invention addresses the above need by providing an improved pharmaceutical composition comprising a macromolecular pharmaceutical agent, an alkali metal alkyl sulfate, and at least three additional micelle-forming compounds, in a suitable solvent. The agent can be one or more proteins, peptides, hormones, vaccines or drugs. The molecular weight of the macromolecular pharmaceutical agent preferably ranges between about 1,000 and 2,000,000 daltons. The agent is presented in mixed micellar form, with a micelle size of approximately one to 10 nanometers (nm). As used herein the term xe2x80x9cmixed micellesxe2x80x9d refers to at least two different types of micelles each of which has been formed using different micelle forming compounds; for example, the present compositions comprise a mix of at least four different types of micellesxe2x80x94micelles formed between the pharmaceutical agent and alkali metal alkyl sulfate, and micelles formed between the pharmaceutical agent and at least three different additional micelle forming compounds as disclosed herein. It will be understood that each individual micelle can be formed from more than one micelle-forming compound as well. The mixed micelles of the present invention tend to be smaller than the pores of the membranes in the oral cavity or the GI tract. It is therefore believed that the extremely small size of the present mixed micelles helps the encapsulated macromolecules penetrate efficiently through the oral mucosae. Thus, the present compositions offer increased bioavailability of active drug, particularly across oral mucosae, when compared with pharmaceutical preparations known in the art.
The present invention is also directed to a method for enhancing the rate of absorption of a macromolecular pharmaceutical agent comprising administering a composition comprising the agent in combination with an alkali metal alkyl sulfate and at least three micelle-forming compounds. Such a method is particularly effective when the composition is administered to the buccal region.
Methods for making and using the present pharmaceutical compositions are also within the scope of the present invention.
It is therefore an aspect of the present invention to provide a pharmaceutical composition comprising a macromolecular pharmaceutical agent and a combination of micelle forming compounds.
It is a further aspect of the invention to provide such a composition wherein the macromolecular pharmaceutical agent is in micellar form.
It is a further aspect of the invention to provide a method for administering macromolecular pharmaceutical agents, particularly to the buccal and pulmonary regions of a patient.
A further aspect of the invention is to provide methods for making pharmaceutical compositions comprising macromolecular pharmaceutical agents and micelle forming compounds.
These and other aspects of the invention will be apparent from the following disclosure and appended claims.
The present invention is directed to a pharmaceutical composition comprising: an effective amount of a macromolecular pharmaceutical agent; an alkali metal alkyl sulfate; at least three micelle-forming compounds selected from the group consisting of lecithin, hyaluronic acid, glycolic acid, lactic acid, chamomile extract, cucumber extract, oleic acid, linoleic acid, linolenic acid, monoolein, monooleates, monolaurates, borage oil, evening of primrose oil, menthol, trihydroxy oxo cholanyl glycine, glycerin, polyglycerin, lysine, polylysine, triolein, polyoxyethylene ethers, polidocanol alkyl ethers, chenodeoxycholate, deoxycholate, pharmaceutically acceptable salts thereof, analogues thereof and mixtures or combinations thereof; and a suitable solvent. The alkali metal alkyl sulfate concentration is between about 0.1 and 20 wt./wt. % of the total composition, each micelle-forming compound concentration is between about 0.1 and 20 wt./wt. % of the total composition, and the total concentration of the alkali metal alkyl sulfate and the micelle-forming compounds together is less than 50 wt./wt. % of the composition.
As used herein, the term xe2x80x9cmacromolecularxe2x80x9d refers to pharmaceutical agents having a molecular weight greater than about 1000 daltons; preferably the macromolecular pharmaceutical agents of the present invention have a molecular weight between about 2000 and 2,000,000 daltons, although even larger molecules are also contemplated.
The term xe2x80x9cpharmaceutical agentxe2x80x9d as used herein covers a wide spectrum of agents, and can include agents used for both human and veterinary applications including but not limited to treatment and study. The term broadly includes proteins, peptides, hormones, vaccines and drugs.
Preferred pharmaceutical agents include insulin, heparin, low molecular weight heparin (molecular weight less than about 5000 daltons), hirulog, hirugen, huridine, interferons, cytokines, mono and polyclonal antibodies, immunoglobins, chemotherapeutic agents, vaccines, glycoproteins, bacterial toxoids, hormones, calcitonins, glucagon like peptides (GLP-1), large molecular antibiotics (i.e., greater than about 1000 daltons), protein based thrombolytic compounds, platelet inhibitors, DNA, RNA, gene therapeutics, antisense oligonucleotides, opioids, narcotics, hypnotics, steroids and pain killers.
Hormones which may be included in the present compositions include but are not limited to thyroids, androgens, estrogens, prostaglandins, somatotropins, gonadotropins, erythropoetin, interferons, steroids and cytokines. Cytokines are small proteins with the properties of locally acting hormones and include, but are not limited to, various forms of interleukin (IL) and growth factors including various forms of transforming growth factor (TGP), fibroblast growth factor (FGF) and insulin-like growth factor (IGF). Vaccines which may be used in the compositions according to the present invention include bacterial and viral vaccines such as vaccines for hepatitis, influenza, tuberculosis, canary pox, chicken pox, measles, mumps, rubella, pneumonia, BCG, HIV and AIDS; bacterial toxoids include but are not limited to diphtheria, tetanus, Pseudomonas sp. and Mycobacterium tuberculosis. Examples of drugs, more specifically cardiovascular or thrombolytic agents, include heparin, hirugen, hirulos and hirudine. Macromolecular pharmaceutical agents included in the present invention further include monoclonal antibodies, polyclonal antibodies and immunoglobins. This list is not intended to be exhaustive.
A preferred macromolecular pharmaceutical agent according to the present invention is insulin. xe2x80x9cInsulinxe2x80x9d as used herein encompasses naturally extracted human insulin, or competently produced human insulin, insulin extracted from bovine, porcine or other mammalian sources, recombinantly produced human, bovine, porcine or other mammalian insulin, insulin analogues, insulin derivatives, and mixtures of any of these insulin products. The term further encompasses the insulin polypeptide in either its substantially purified form, or in its commercially available form in which additional excipients are added. Various form of insulin are widely commercially available. An xe2x80x9cinsulin analoguexe2x80x9d encompasses any of the insulins defined above wherein one or more of the amino acids within the polypeptide chain has been replaced with an alternative amino acid, wherein one or more of the amino acids have been deleted, or wherein one or more amino acids is added. xe2x80x9cDerivativesxe2x80x9d of insulin refers to insulin or analogues thereof wherein at least one organic substituent is bound to one or more of the amino acids in the insulin chain.
The macromolecular pharmaceutical agent exists in micellar form in the present pharmaceutical compositions. As will be appreciated by those skilled in the art, a micelle is a colloidal aggregate of amphipathic molecules in which the polar hydrophilic portions of the molecule extend outwardly while the non-polar hydrophobic portions extend inwardly. As discussed below, various combinations of micelle-forming compounds are utilized in order to achieve the present formulation. It is believed that the presence of the micelles significantly aids in the absorption of the macromolecular pharmaceutical agent both because of their enhanced absorption ability, and also because of their size. In addition, encapsulating pharmaceutical agents in micelles protects the agents from rapid degradation in the GI environment.
The particle size of the micelles will typically be in the range of 1 to 10 nanometers, many will range between 1 and 5 nanometers in size. The shape of the micelle can vary and can be, for example, prolate, oblate or spherical; spherical micelles are most typical.
An effective amount of the macromolecular pharmaceutical agent should be included in the present composition. As used herein, the term xe2x80x9ceffective amountxe2x80x9d refers to that amount of the pharmaceutical agent needed to bring about the desired result, such as obtaining the intended treatment or prevention of a disorder in a patient, or regulating a physiological condition in a patient. Such an amount will therefore be understood as having a therapeutic and/or prophylactic effect in a patient. As used herein, the term xe2x80x9cpatientxe2x80x9d refers to members of the animal kingdom, including but not limited to humans. It will be appreciated that the effective amount will vary depending on the particular agent used, the parameters determined for the agent, the nature and severity of the disorder being treated, the patient being treated, and the route of administration. The determination of what constitutes an effective amount is well within the skill of one practicing in the art. Typically, the present formulations will contain pharmaceutical agents in a concentration between about 0.1 and 20 wt./wt. % of the total composition, more preferably between about 1 and 10 wt./wt. %.
Any alkali metal alkyl sulfate can be used in the present compositions, provided compatibility problems do not arise. Preferably, the alkyl is a C8 to C22 alkyl, more preferably lauryl (C12). Any alkali metal can be utilized, with sodium being preferred. The alkali metal alkyl sulfate is generally present in a concentration of between about 0.1 and 20 wt./wt. % of the total composition; a concentration of less than about 5 wt./wt. % of the total composition is preferred.
The compositions of the present invention further comprise at least three micelle-forming compounds selected from the group comprising lecithin, hyaluronic acid, glycolic acid, lactic acid, chamomile extract, cucumber extract, oleic acid, linoleic acid, linolenic acid, monoolein, monooleates, monolaurates, borage oil, evening of primrose oil, menthol, trihydroxy oxocholanyl glycine, glycerin, polyglycerin, lysine, polylysine, triolein, polyoxyethylene ethers, polidocanol alkyl ethers, chenodeoxycholate and deoxycholate. Pharmaceutically acceptable salts and analogues of any of these compounds are also within the present scope as are mixtures or combinations of any of these compounds. Each of the three, or more, micelle-forming compounds listed above is present in the compositions in a concentration of between about 0.1 and 20 wt./wt. % of the total composition. More preferably, each of these micelle-forming compounds is present in a concentration of less than about 5 wt./wt. % of the total composition. For delivery of the present macromolecular pharmaceutical agents, particularly insulin, use of three or more micelle-forming compounds achieves a cumulative effect in which the amount of pharmaceutical agent that can be delivered is greatly increased as compared to when only one or two micelle-forming compounds are used. Use of three or more micelle-forming compounds also enhances the stability of the pharmaceutical agent compositions.
The alkali metal alkyl sulfate functions as a micelle forming agent, and is added to the composition in addition to the three or more other micelle-forming compounds listed herein. The total concentration of alkali metal alkyl sulfate and the three or more additional micelle-forming compounds together is less than 50 wt./wt. % of the composition.
It will be appreciated that several of the micelle-forming compounds are generally described as fatty acids, bile acids, or salts thereof. The best micelle-forming compounds to use may vary depending on the pharmaceutical agent used and can be readily determined by one skilled in the art. In general, bile salts are especially suitable for use with hydrophilic drugs and fatty acid salts are especially suitable for use with lipophilic drugs. Because the present invention uses relatively low concentrations of bile salts, problems of toxicity associated with the use of these salts is minimized, if not avoided.
The lecithin can be saturated or unsaturated, and is preferably selected from the group consisting of phosphatidylcholine, phosphatidylserine, sphingomyelin, phosphatidylethanolamine, cephalin, and lysolecithin.
Preferred salts of hyaluronic acid are alkali metal hyaluronates, especially sodium hyaluronate, alkaline earth hyaluronates, and aluminum hyaluronate. When using hyaluronic acid or pharmaceutically acceptable salts thereof in the present compositions, a concentration of between about 0.1 and 5 wt./wt. % of the total composition is preferred, more preferably less than about 3.5 wt./wt. %.
Particularly suitable micelle-forming compound combinations include i) sodium hyaluronate, monoolein and saturated phospholipid, ii) saturated phospholipid, monoolein and glycolic acid, iii) sodium hyaluronate, polyoxyethylene ether and lecithin, iv) polyoxyethylene ether, trihydroxy oxocholanyl glycine and lecithin, v) polidocanol 9 lauryl ether, polylysine and triolein, vi) saturated phospholipid, polyoxyethylene ether and glycolic acid, vii) trihydroxy oxocholanyl glycine, lecithin and chenodeoxycholate; viii) trihydroxy oxocholanyl glycine, deoxycholate and glycerin; ix) polidocanol 10 lauryl ether, sodium oxocholanyl glycine and lecithin; x) polidocanol 10 lauryl ether, phosphatidyl choline and oleic acid; xi) polidocanol 10 lauryl ether, sodium hyaluronate and lecithin; and xii) polidocanol 20 lauryl ether, evening of primrose oil and lecithin.
The above-described components of the present composition are contained in a suitable solvent. The term xe2x80x9csuitable solventxe2x80x9d is used herein to refer to any solvent in which the components of the present invention can be solubilized, in which compatibility problems do not arise, and which can be administered to a patient. Any suitable aqueous or nonaqueous solvent can be used. A particular preferred solvent is water. Other suitable solvents include alcohol solutions, especially ethanol. Alcohol should be used at concentrations that will avoid precipitation of the components of the present compositions. Enough of the solvent should be added so that the total of all of the components in the composition is 100 wt./wt. %, i.e., solvent to q.s. Typically, some portion of the solvent will be used initially to solubilize the pharmaceutical agent prior to the addition of the micelle-forming compounds.
The present compositions optionally contain a stabilizer and/or a preservative. Phenolic compounds are particularly suited for this purpose as they not only stabilize the composition, but they also protect against bacterial growth and help absorption of the composition. A phenolic compound will be understood as referring to a compound having one or more hydroxy groups attached directly to a benzene ring. Preferred phenolic compounds according to the present invention include phenol and methyl phenol (also known as m-cresol), and mixtures thereof. hyaluronate. When using hyaluronic acid or pharmaceutically acceptable salts thereof in the present compositions, a concentration of between about 0.1 and 5 wt./wt. % of the total composition is preferred, more preferably less than about 1.5 and 3.5 wt./wt.
Particularly suitable micelle-forming compound combinations include i) sodium hyaluronate, monoolein and saturated phospholipid, ii) saturated phospholipid, monoolein and glycolic acid, iii) sodium hyaluronate, polyoxyethylene ether and lecithin, iv) polyoxyethylene ether, trihydroxy oxocholanyl glycine and lecithin, v) polidocanol 9 lauryl ether, polylysine and triolein, vi) saturated phospholipid, polyoxyethylene ether and glycolic acid, vii) trihydroxy oxocholanyl glycine, lecithin and chenodeoxycholate; viii) trihydroxy oxocholanyl glycine, deoxycholate and glycerin; ix) polidocanol 10 lauryl ether, sodium oxocholanyl glycine and lecithin; x) polidocanol 10 lauryl ether, phosphatidyl choline and oleic acid; xi) polidocanol 10 lauryl ether, sodium hyaluronate and lecithin; and xii) polidocanol 20 lauryl ether, evening of primrose oil and lecithin.
The above-described components of the present composition are contained in a suitable solvent. The term xe2x80x9csuitable solventxe2x80x9d is used herein to refer to any solvent in which the components of the present invention can be solubilized, in which compatibility problems do not arise, and which can be administered to a patient. Any suitable aqueous or nonaqueous solvent can be used. A particular preferred solvent is water. Other suitable solvents include alcohol solutions, especially ethanol. Alcohol should be used at concentrations that will avoid precipitation of the components of the present compositions. Enough of the solvent should be added so that the total of all of the components in the composition is 100 wt./wt. %, i.e., solvent to q.s. Typically, some portion of the solvent will be used initially to solubilize the pharmaceutical agent prior to the addition of the micelle-forming compounds.
The present compositions optionally contain a stabilizer and/or a preservative. Phenolic compounds are particularly suited for this purpose as they not only stabilize the composition, but they also protect against bacterial growth and help absorption of the composition. A phenolic compound will be understood as referring to a compound having one or more hydroxy groups attached directly to a benzene ring. Preferred phenolic compounds according to the present invention include phenol and methyl phenol (also known as m-cresol), and mixtures thereof.
The compositions of the present invention can further comprise one or more of the following: inorganic salts; antioxidants; protease inhibitors; and isotonic agents. The amount of any of these optional ingredients to use in the present compositions can be determined by one skilled in the art. It will be understood by those skilled in the art that colorants, flavoring agents and non-therapeutic amounts of other compounds may also be included in the formulation. Typical flavoring agents are menthol, sorbitol and fruit flavours. When menthol is used as one of the micelle-forming compounds, therefore, it will also impart flavor to the composition.
For example, some compositions, including those which contain insulin, may also contain at least one inorganic salt; the salt should be one which opens channels in the GI tract and which may provide additional stimulation to release insulin. Non-limiting examples of inorganic salts are sodium, potassium, calcium and zinc salts, especially sodium chloride, potassium chloride, calcium chloride, zinc chloride and sodium bicarbonate.
It will be recognized by those skilled in the art that for many pharmaceutical compositions it is usual to add at least one antioxidant to prevent degradation and oxidation of the pharmaceutically active ingredients. The antioxidant can be selected from the group consisting of tocopherol, deteroxime mesylate, methyl paraben, ethyl paraben, ascorbic acid and mixtures thereof, as well as other antioxidants known in the pharmaceutical arts. A preferred antioxidant is tocopherol. The parabens will also provide preservation to the composition.
Protease inhibitors serve to inhibit degradation of the pharmaceutical agent by the action of proteolytic enzymes. When used, protease inhibitors are preferably in a concentration of between about 0.1 and 3 wt./wt. % of the composition. Any material that can inhibit proteolytic activity can be used, absent compatibility problems. Examples include but are not limited to bacitracin and bacitracin derivatives such as bacitracin methylene disalicylates, soybean trypsin, and aprotinin. Bacitracin and its derivatives are preferably used in a concentration of between 1.5 and 2 wt./wt. % of the total composition, while soyabean trypsin and aprotinin are preferably used in a concentration of between about 1 and 2 wt./wt. % of the total composition.
An isotonic agent such as glycerin or dibasic sodium phosphate may also be added after formation of the mixed micellar composition. The isotonic agent serves to keep the micelles in solution. When glycerin is used as one of the micelle-forming compounds it will also function as an isotonic agent. When dibasic sodium phosphate is used it will also serve to inhibit bacterial growth.
The pH of the present pharmaceutical composition should typically be in the range of 5 to 8, more preferably 6 to 7. Hydrochloric acid or sodium hydroxide can be utilized to adjust the pH of the composition as needed.
The compositions of the present invention may be stored at room temperature or at cold temperature. Storage of proteinic drugs is preferable at a cold temperature to prevent degradation of the drugs and to extend their shelf life.
The present invention, therefore, provides a pharmaceutical composition in which a macromolecular pharmaceutical agent is encapsulated in mixed micelles formed by a combination of micelle-forming agents. The composition can be delivered through buccal or pulmonary means, with buccal being preferred. Both the oral and nasal membranes offer delivery advantages, in that drugs administered through these membranes have a rapid drug absorption and a rapid onset of action, provide therapeutic plasma levels, avoid the first pass effect of hepatic metabolism, and avoid exposure of the drug to the hostile GI environment. An additional advantage is the easy access to membrane sites, so that the drug can be applied, localized and removed easily.
Oral routes of administration may be particularly advantageous. The sublingual mucosa includes the membrane of the ventral surface of the tongue and the floor of the mouth, and the buccal mucosa is the lining of the cheeks. The sublingual and buccal mucosae are relatively permeable, allowing for the rapid absorption and acceptable bioavailability of many drugs. Further, the buccal and sublingual mucosae are convenient, non-evasive and easily accessible. In comparison to the GI tract and other organs, the buccal environment has lower enzymatic activity and a neutral pH that allows for a longer effective life of the drug in vivo. The sublingual mucosa and buccal mucosa are collectively referred to herein as the xe2x80x9coral mucosaexe2x80x9d.
It is believed that improvements in penetration and absorption of the present mixed micellar formulations can be achieved by administering the present compositions with propellants such as tetrafluoroethane, heptafluoroethane, dimethylfluoropropane, tetrafluoropropane, butane, isobutane, dimethyl ether and other non-CFC and CFC propellants. Preferably, the ratio of pharmaceutical agent to propellant is from 5:95 to 25:75. The preferred propellants are hydrogen-containing chlorofluorocarbons, hydrogen-containing fluorocarbons, dimethyl ether and diethyl ether. Even more preferred is HFA-134 a (1,1,1,2-tetrafluoroethane).
Preferably, the present compositions are delivered through metered dose inhalers or spray devices. Metered dose inhalers are known and are a popular pulmonary drug delivery form for some drugs. One benefit of using a metered dose device is the ability to deliver a precise amount of medication with each application, and another is that the potential for contamination is minimized because the devices are self-contained.
The present invention also provides a process for making the pharmaceutical composition of the present invention. The present compositions may be prepared by mixing a solution of the macromolecular pharmaceutical agent, the alkali metal alkyl sulfate, at least three micelle-forming compounds, and optionally the stabilizer and other additives. The pharmaceutical agent should be added in an amount effective for the desired purpose. The micelle-forming compounds may be added concurrently or sequentially. Mixed micelles will form with substantially any kind of mixing of the ingredients but vigorous mixing is preferred in order to provide micelles of about 10 nanometers or less in size. The pharmaceutical agents, solvents, alkali metal alkyl sulfates, micelle-forming compounds and optional additives as described above for the present compositions are all suitable for use in the present processes.
In one method a first micellar composition is prepared by mixing a solution comprising the pharmaceutically active agent with at least the alkali metal alkyl sulfate to form the first micellar composition. The first micellar composition is then mixed with at least three additional micelle-forming compounds to form a mixed micellar composition. In another method, a first micellar composition is prepared by mixing a solution containing the pharmaceutically active agent, the alkali metal alkyl sulfate and at least one additional micelle-forming compound; to the composition is then added the remaining micelle-forming compounds, with vigorous mixing. The alkali metal alkyl sulfate and three or more micelle-forming compounds should not be added to the pharmaceutical agent solution all at once.
The stabilizer, preferably phenol and/or m-cresol, may be added to the mixed micellar composition to stabilize the formulation and protect against bacterial growth. Alternatively, the stabilizer may be added at the same time as any of the micelle-forming ingredients. An isotonic agent may also be added after formation of the mixed micellar composition. Similarly, any of the other optional additives as described above can be added at this time. The formulation can then be put into an aerosol dispenser and the dispenser charged with propellant, if administration by this route is desired. The propellant, which is under pressure, is in liquid form in the dispenser. When the composition of the present invention is in a dispenser, the aqueous phase may be separated from the propellant phase. Preferably, however, the ratios of the ingredients are adjusted by simple experimentation so that the aqueous and propellant phases become one, i.e., there is one phase. If there are two phases, it may be necessary to shake the dispenser prior to dispensing a portion of the contents, such as through a metered valve. The dispensed dose of pharmaceutical agent is propelled from the metered valve in a fine spray.
One specific embodiment of the present processes provides for making the present pharmaceutical compositions by:
a) mixing a macromolecular pharmaceutical agent in a suitable solvent with an alkali metal alkyl sulfate, and adding to the mixture at least three micelle-forming compounds selected from the group consisting of lecithin, hyaluronic acid, glycolic acid, lactic acid, chamomile extract, cucumber extract, oleic acid, linoleic acid, linolenic acid, monoolein, monooleates, monolaurates, borage oil, evening of primrose oil, menthol, trihydroxy oxo cholanyl glycine, glycerin, polyglycerin, lysine, polylysine, triolein, polyoxyethylene ethers, polidocanol alkyl ethers, chenodeoxycholate, deoxycholate, pharmaceutically acceptable salts thereof, analogues thereof, and mixtures or combinations thereof, to form a mixed micellar macromolecular pharmaceutical agent composition.
Each of the micelle-forming compounds, including the alkali metal alkyl sulfate, is in a concentration of from 0.1 to 20 wt./wt. % of the total composition, with the total being less than 50 wt./wt. % of the total composition.
The method can further comprise the step of adding a stabilizer such as a phenolic compound selected from the group phenol, m-cresol and mixtures thereof; the addition of the stabilizer can be either before, during, or after the addition of the alkali metal alkyl sulfate, or before, during or after the addition of the micelle-forming compounds.
The method can further comprise the step of placing the composition into an aerosol dispenser and charging the dispenser with a propellant.
In another specific embodiment, the process comprises:
a) mixing a macromolecular pharmaceutical agent in a suitable solvent with an alkali metal alkyl sulfate, and at least one micelle-forming compound selected from the group consisting of lecithin, hyaluronic acid, glycolic acid, lactic acid, chamomile extract, cucumber extract, oleic acid, linoleic acid, linolenic acid, monoolein, monooleates, monolaurates, borage oil, evening of primrose oil, menthol, trihydroxy oxo cholanyl glycine, glycerin, polyglycerin, lysine, polylysine, triolein, polydocano alkyl ethers, polidocanol alkyl ethers, chenodeoxycholate, deoxycholate, pharmaceutically acceptable salts thereof, analogues thereof, and mixtures or combinations thereof, to form a first mixed micellar macromolecular pharmaceutical agent composition; and
b) adding at least two micelle-forming compounds to the first composition that are different from that added in step a) but selected from the same group.
Again, during or after step a), a stabilizer as described above can be added to the composition. Mixing can be vigorous or not. Vigorous mixing may be accomplished by using high-speed stirrers, such as magnetic stirrers, propeller stirrers, or sonicators, and is preferred.
The present invention also provides a metered dose aerosol dispenser with the composition of the present invention and a propellant contained therein, in which a solution containing the macromolecular pharmaceutical agent and the propellant are in a single phase.
The present invention also provides a method for administering the pharmaceutical compositions of the present invention, by spraying the intermixed composition into the mouth with a metered dose spray device. Application can be to the buccal cavity by spraying into the cavity, without inhalation. It may be necessary or desirable to shake the dispenser prior to spraying the present pharmaceutical composition and propellant into the buccal cavity. The plasma levels and blood glucose levels when orally administering the present insulin-containing compositions are comparable to those achieved when insulin is injected; the present methods offer significant improvements in the quality of life over injection including pain-free and needle-free therapy and improved convenience.
In the case of insulin, which is intended for administration through the mouth cavity, a first micellar solution may be made by adding water or other solvent, and then hydrochloric acid (typically 5M) to powdered insulin, and stirring until the powder is dissolved and a clear solution is obtained. The solution can then neutralized with sodium hydroxide. A sodium alkyl sulfate may be added to the neutralized solution with low speed stirring, either alone or with at least one micelle forming compound. A typical concentration of sodium lauryl sulfate, as the sodium alkyl sulfate, in the aqueous solution is less than about 5 wt./wt. % of the solution. Typically, insulin is present in the micellar solution in an amount which will give a concentration of about 0.1 to 20 wt./wt. % of the final composition.
The solution so formed may then be mixed vigorously, such as by sonication or high speed stirring, to form a micelle solution. Other micelle forming compounds, as described above, may then be added. The mixing may be done with a high-speed mixer or sonicator to ensure uniform micelle particle size distribution within the composition.
In a preferred embodiment, after forming the present micellar pharmaceutical compositions, the phenol and/or m-cresol is added. As indicated above, other ingredients, such as isotonic agents, flavoring agents, anti-oxidants, salts, protease inhibitors or other pharmaceutically acceptable compounds may also be added to an aerosol dispenser. The formulation can be placed in an aerosol dispenser, and the dispenser charged with propellant in a known manner.
The specific concentrations of the above ingredients can be determined by one skilled in the art based upon the general guidelines provided herein. It will be understood that the amounts of certain ingredients may need to be limited in order to avoid compositions which produce foam when sprayed rather than forming a fine spray. For absorption through the oral cavities, it is often desirable to increase, such as by doubling or tripling, the dosage of pharmaceutical agent which is normally required through injection or administration through the gastrointestinal tract.
The desired size of aerosol droplets which are sprayed from the aerosol dispenser will depend, in part, on where the pharmaceutical is to be deposited. For example, for deposition in the lungs, particle sizes of less than about 5 xcexcm are preferred whereas for absorption in the buccal cavity of the mouth, particle sizes of about 5-10 xcexcm are preferred.
The present invention is also directed to a method for enhancing the rate of absorption of a macromolecular pharmaceutical agent comprising administering a composition comprising said agent in conjunction with an alkali metal alkyl sulfate and at least three of the micelle-forming compounds described above. Preferably, this method is carried out by administering directly to the buccal region of the patient.
Administration of the formulation into the buccal cavity, according to any of the present methods, is by spraying the formulation into the mouth, without inhalation, so that the droplets stay in the mouth rather than being drawn into the lungs.